Telomere length can vary substantially among individuals, and recent data show that this length variation correlates with age-dependent mortality from infectious and cardiovacular diseases. Since in humans, as in all eukaryotic organisms with linear chromosomes, telomere length depends on a highly conserved mechanism for maintenance of chromosome termini, our ultimate goal is to test whether natural genetic variation in multiple telomere maintenance genes contributes to age-related diseases and mortality. However, identifying such causative variation in multiple genes, by comparative standard SNP analysis of age-matched cohorts, is a formidable challenge. This application targets a subset of telomere maintenance genes that are conserved in yeast and humans, and presents a potential methodological solution to the problem of identifying causative genetic variation. A multidisciplinary approach combines a new computational method, called the Evolutionary Trace (ET), that identifies patterns of sequence variation that correlate with functional divergence, with in vivo modeling in yeast cells of the "fitness" of genetic variation in genes that are required for telomere function. Our goals are to test whether a functional correlation can be established between naturally occurring genetic variation in conserved telomere maintenance genes and effects on cellular proliferation; and whether ET can identify functionally important cSNPs in the human versions of the 8 telomere maintenance genes selected for this study. If so, this will enable larger scale telomere maintenance/disease-association studies that will now be feasible because they will focus on a subset of polymorphisms. More generally, it will provide proof of principle that human polymorphisms can be initially screened computationally for their functional importance based on evolutionary analysis. This will, we hope, set the stage for elucidating the target(s) of telomere-based human aging, with the potential for clinical intervention to alleviate the onset of at least some age-dependent diseases.